1. Field of the Invention
The present invention relates to an enantioselective Reformatsky process for preparing optically active alcohols, amines and derivatives thereof.
2. The Prior Art
The reaction of reactive halogen compounds, in particular α-halo carbonyl compounds, with electrophilic substrates, for example aldehydes, ketones or imines, in the presence of a zinc metal, is known as the Reformatsky reaction. This affords important synthetic building blocks for the preparation of active pharmaceutical ingredients, scents and crop protection agents.
Asymmetric Reformatsky reactions for the targeted preparation of enantiomerically pure synthetic building blocks, for example alcohols and amines, are becoming ever more important.
For example, M. Guette, J. Capillon, J.-P. Guette, Tetrahedron, 1973, 29, p. 3659 disclose an enantioselective Reformatsky synthesis of (S)-(−)-3-hydroxy-3-phenylpropionic esters using benzaldehyde as the substrate in the presence of the chiral ligand (−)-sparteine in the relatively noncoordinating solvents benzene and dimethoxymethane. Although the process provides high enantioselectivities of up to 95±3% ee, only very low chemical yields of a maximum of 38 i 7% of theory could be achieved.
Pedrosa et al. (J. M. Andres, Y. Martin, R. Pedrosa, A. P,rez-Encabo, Tetrahedron, 1997, 53, p. 3787) describe an enantioselective Reformatsky reaction for preparing optically active β-hydroxy esters using amino alcohols as chiral auxiliaries in tetrahydrofuran.
However, high chemical yields of up to 90% are achieved at only moderate enantioselectivities of from 22 to 62% ee. In addition, the process is based on the use of large excesses of the organozinc compound (Reformatsky reagent) and is therefore of little interest from an economic and industrial point of view.
Seebach et al. (D. Seebach, W. Langer, Helv. Chim. Acta 1979, 62, p. 1701) describe an enantioselective Reformatsky reaction using chiral diamines as cosolvents with good chemical yields of up to 95%, but only small enantiomeric excesses of a maximum of 24.5% ee.
Ojida et al. (A. Ojida, T. Yamano, N. Taya, A. Tasaka, Org. Lett. 2002, 4, p. 3051) describe an enantioselective Reformatsky process using cinchona amino alcohols as chiral ligands and ketones as substrates. High enantioselectivities (up to 97% ee) could only be achieved where an sp2 nitrogen atom adjacent to the carbonyl group of the ketone substrate makes chelation of the zinc possible. Other ketone substrates and aldehydes as electrophilic substrates deliver only moderate optical yields of 15-70% ee. In addition, the process requires a large excess of Reformatsky reagent and expensive pyridine as a basic assistant, which means that the process is of little interest from an economic and industrial point of view.
Ukaji et al. (Y. Ukaji, S. Takenaka, Y. Horita, K. Inomata, Chem. Lett. 2001, p. 254) describe an enantioselective Reformatsky process for preparing optically active β-amino acid esters using diisopropyl tartrate as a chiral auxiliary. Even though enantioselectivities of up to 98% ee and yields of up to 80% could be achieved, the process requires the use of large excesses both of the organozinc compound (diethylzinc) and of very expensive iodoacetic ester. This process is therefore unsuitable for preparing optically active β-amino acid esters from an economic and industrial point of view.
None of the existing processes delivers both high chemical and high optical yields while economically using reagents used, in particular organozinc compounds. The prior art processes are therefore unsuitable in particular for economic and industrial scale synthesis of optically active alcohols and amines.